Insulin dependent diabetes mellitus results from the autoimmune destruction of the pancreatic beta cells. Once these crucial cells are lost they cannot be regained since the adult pancreas lacks the ability for regrowth. Therefore, IDDM patients are dependent on the possibility of receiving new endocrine cells to cure their disease. One therapy for IDDM patients is the possibility of utilizing islet progenitor cells for the in vivo or in vitro growth of new pancreatic islets. Indeed these cells could represent a limitless supply of differentiated beta cells for IDDM patients. However the exact identity of islet progenitor cells remains unknown despite dramatic progress in the area of islet ontogeny in recent years. Our laboratory has defined a novel cell surface antigen that is expressed on a cell population in the regenerating pancreas as well as in the normal adult small intestine, facilitating their purification. In this application we show that sorted intestinal cells give rise to insulin-producing cells following in vivo transfer experiments. This work suggests that stem cells that can give rise to functional islets can exist in the normal adult gut. Importantly, we have found in our preliminary studies that the transfer of sorted adult intestinal cells into STZ-treated diabetic mice significantly improves their blood glucose levels. The overall goal of this application is to develop these findings into a new therapy for clinical IDDM patients. This application is Bench to Bedside Partnership between investigators at Scripps Research Institute: Drs. Sarvetnick, Kritzik, Solomon, and Dabernat; Whittier Institute: Dr. Alberto Hayek; City of Hope National Medical Center Islet Cell Resource Center: Dr. Fouad Kandeel, and an outside consultant: Dr. Ronnda Bartel. The experiments proposed are designed to optimize conditions for the expansion of these intestinal-derived progenitor cells in vitro, an important consideration given the limited supply of donor cells. We will utilize the expanded cells in transfer experiments to assess their differentiation potential in vivo. Subsequently, we will define conditions for the intestinal cells to incorporate and expand in diabetic mice, optimizing conditions for their transfer, incorporation, and differentiation in the recipient. The proposed studies will allow the development of a new strategy for the isolation and expansion of intestinal islet progenitor cells, and their subsequent use in the treatment of diabetic conditions, which are clearly important goals for the establishment of therapies for IDDM patients.